What is New in Type 1 Diabetes? Prof. Åke Lernmark

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1 What is New in Type 1 Diabetes? Lunds Universitet/CRC Skånes University Hospital SUS Malmö, Sweden 1 What s new in type 1 diabetes? Is the disease still increasing? What is the etiology? What is the pathogenesis? Is type 1 diabetes predictable? 2 Type 1 diabetes is increasing 3-5% per year Incidence /100,000/ yr in children 0-14 yr 3 TEDDY; Ann NYAS

2 New cases of type 1 diabetes in children, 0-14 years (cases per 100,000 aged 0-14 years per year), 2010 MAP 2.4 Improved quality of life Type 1 diabetes is increasing 4 What s new in type 1 diabetes? Is the disease still increasing? What is the etiology? What is the pathogenesis? Is type 1 diabetes predictable? 5 Genetic etiology: inheritance of genetic risk Immune cells: APC (DC) T cells B cells 6 Från Joerg Ermann & C. Garrison Fathman Nature Immunology 2: (2001) 2

3 Red: insulin Blue: glucagon Green: somatostatin 7 Markers of islet autoimmunity Insulin autoantibodies (IAA) 1983 GAD65 autoantibodies (GAD65Ab) K 1990 GAD 1991 GAD65 I-A2/IA-2b autoantibodies (IA-2Ab) 1994 ZnT8 transporter autoantibodies (ZnT8Ab) 2007 GAD65Ab and IA-2Ab standardized in 1998 WHO standard (RA from Linköping) is used since Type 1 diabetes is a two step disease HLA-DQ A1-B IA-2Ab IAA Genetic susceptiblity Islet autoimmunity Type 1 Diabetes GAD65Ab ZnT8Ab Trigger(s) 9 3

4 Generation of autoimmunity: primary autoantigen processing? HLA-DQ2 HLA-DQ8 8/2 8/8 8/6.4 8/5.1 Islet autoantigen(s) Beta-cell death Autophagy Apoptosis Necrosis Virus infection(s)? 10 HLA-DQ8 and insulin peptide 11 HLA-A2 and insulin 12 4

5 B lymphocytes and autoantibodies 13 Preservation of insulin secretion with Rituximab Similar effects are observed with CD3 mabs C-peptide pmol/ml * * * Overall p < Rituximab Placebo Time in months Means and 95% CL Adjusted for baseline C-peptide, age and sex 14 MHC class II variability 15 DQ8 DR3-DQ2 DQ6.4 Insulin autoantibodies IA-2 autoantibodies GAD65 autoantibodies ZnT8 autoantibodies 5

6 Type 1 diabetes is a two step disease HLA-DQ A1-B IA-2Ab IAA Genetic susceptiblity Islet autoimmunity Type 1 Diabetes GAD65Ab ZnT8Ab Trigger(s) 16 The environmental determinants of diabetes in the young (TEDDY) study NIH consortium initiated September 2004 screening completed February 2010 TEDDY primary goals: 1. To identify environmental factors causing pre-diabetic islet autoimmunity and T1D 2. To assess potential gene-environment interactions and to gain insight on mechanisms 17 Birth Screening HLA-DQ genotypes 420,000 newborns screened Follow-up 8600 children Infections: Other factors: Virus Diet Bacteria Toxins Vaccinations Psychosocial factors US CO GE/FL WA EUROPA: FIN GER SWE 15 years 18 Islet autoimmunity T1D n ~400 6

7 Enrollment by HLA genotype - all subjects DQ2/2 DQ2/8 DQ4/8 DQ8/8 GPN = 7,755 enrolled (39%), 19,906 eligible (4.8%), 414,714 screened FDR N =915 enrolled (65%), 1,415 eligible (22%), 6,333 screened 19 Final 2010 The Environmental Determinants of Diabetes in the Young TEDDY follow-up protocol Interviews: diet, infections, immunizations, day care, etc. Samples of blood q3 months: autoantibodies, biomarkers, DNA, T-cells, mrna, microbial abs Stool q1 month: entero-, rota-virus, bacteria 20 TEDDY children with islet autoantibodies Number ab+ children 100 Total 360 children Sweden Finland Colorado Germany Washington Fl/Georgia The Environmental Determinants 21 of Diabetes in the Young 7

8 Number of islet autoantibodies more common to have more than one Number of positive antibodies antibody 2-3 antibodies The Environmental Determinants 22 of Diabetes in the Young 20% Finnish children develop islet autoantibodies earlier p = 0.01 Log rank test 10% Finland Sweden Germany USA 23 Persistent islet autoimmunity in first-degree relatives 20% Finland Germany Sweden 10% U.S. p = Log rank test 24 8

9 Gestational infections may contribute Dahlquist G, Frisk G, Ivarsson SA, Svanberg L, Forsgren M, Diderholm H. Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM; Diabetologia 38: , 1995 Eising S, Nilsson A, Carstensen B, Hougaard DM, Norgaard-Petersen B, Nerup J, et al. Danish children born with GAD65 and IA-2 autoantibodies at birth had an increased risk to develop type 1 diabetes before 2004; Eur J Endocrinol 2010 Nov 19 Lindehammer SR, Hansson I, Midberg B, Ivarsson SA, Lynch KF, Dillner J, et al. Seroconversion to islet autoantibodies between early pregnancy and delivery in non-diabetic mothers; J Reprod Immunol 88: 72-9, Future study <14 th week >14 th 23 rd week 25 th 28 th week Early pregnancy * * * * * Second trimester HLA typing Birth Trigger(s) Blood sample * 26 What s new in type 1 diabetes? Is the disease still increasing? What is the etiology? What is the pathogenesis? Is type 1 diabetes predictable? 27 9

10 HLA-DQ A1-B IA-2Ab IAA Genetic susceptiblity Islet autoimmunity Type 1 Diabetes Trigger(s) GAD65Ab ZnT8Ab Accelerators 28 T1D children by site Finland 25 Sweden Colorado Germany 7 Washington 4 Georgia/Fl The Environmental Determinants 29 of Diabetes in the Young More antibodies = greater risk Survival Distribution Function ab 3 ab 1 ab 2 ab Years Followed 8 10

11 A subject in DiPiS Diabetes after 9 years Age (Years) Age (Years) 31 Age (Years) Age (Years) HLA class II presents antigens 1) Phagocytosis/pinocytosis 2) Antigen processing 1) Specific Ag uptake via Fc receptor 2) Antigen processing 3) Antigen presentation 3) Antigen presentation 32 Standard antigen presentation Autoantibody-mediated Antigen presentation Antigen recognition by CD8+ T cells T cell Vb T cell receptor Class I MHC b2m Va CD8+ T cells attack beta-cells not the beginning but the end of a long period of islet autoimmunity!! 33 After T. DiLorenzo b cell 11

12 Type 1 diabetes is a two step disease Insulitis and onset of hyperglycemia happen after months/years of islet autoimmunity HLA-DQ A1-B IA-2Ab IAA Insulitis Genetic susceptiblity Islet autoimmunity Type 1 Diabetes Trigger(s) GAD65Ab ZnT8Ab Accelerators 34 What s new in type 1 diabetes? Is the disease still increasing? What is the etiology? What is the pathogenesis? Is type 1 diabetes predictable? 35 More antibodies = greater risk Survival Distribution Function ab 3 ab 1 ab 2 ab Years Followed 8 12

13 Is type 1 diabetes a predictable disease? Autoantibodies are strong warning signals Four islet autoantibodies results in diabetes in 50% within three years Islet autoantibodies may be used to select subjects for prevention clinical trials 37 DKA prevalence No DKA = ph>7.3 neg urine or blood ketones no symptoms physicians diagnosis No DKA n=86 90% (n=69 by ph) DKA n=9 9% Unkown n =1 1 % Severe DKA (ph<7.1) n=3 3% The Environmental Determinants 38 of Diabetes in the Young Diabetes care Reduced Prevalence of Diabetic Ketoacidosis at Diagnosis of Type 1 Diabetes in Young Children Participating in Longitudinal Follow-Up Larsson HE, Vehik K, Bell R, Dabelea D, Dolan L Pihoker C, Knip M Veijola R, Lindblad B, Samuelsson U, Holl R, and MJ Haller on behalf of the TEDDY, SEARCH, Swediabkids, DPV, and Finnish Diabetes Registry Study Groups; Diabetes Care; Oct 4, 2011 PMID: The Environmental Determinants of Diabetes in the Young 13

14 Total DKA Mild DKA Severe DKA Study Under 2 P Under 5 P Under 2 P Under 5 P Under 2 P Under 5 P TEDDY Strict Definition 5/ % 8/ % 2/31 6.5% 5/61 8.2% 3/31 9.7% 3/61 4.9% TEDDY Broad Definition 6/40 15% 9/ % 3/40 7.5% 6/79 7.6% 3/40 7.5% 3/79 3.8% Sweden Registry 51/ % / % / % / % 12/ % / % 0.73 SEARCH 29/ % < / % <0.001 N/A N/A N/A N/A N/A N/A N/A N/A Finland Registry 82/ % < / % / % / % / % / % 0.74 German Registry /435 54% < / % < / % < / % 64/435 < % / % 0.36 OGTT and T1D 19/93 children diagnosed with T1D had OGTT done before diagnosis 13/19 diagnosed by the OGTT Children with T1D who had OGTT done/site Ger Fl/GA Was Col Fin Swe Benefits of early diagnosis are tested with long-term preservation of residual beta-cell function The Environmental Determinants 41 of Diabetes in the Young Conclusions Worldwide epidemic The Trigger of islet autoimmunity remains to be identified Subclinical islet autoimmunity should be recognized Should it be treated? B lymphocytes may be the target as they serve as APC for chronic islet autoimmunity Islet autoimmunity allows early detection of type 1 diabetes; Prevents DKA 42 14

15 Helena Larsson Caroline Nilsson Corrado Cilio Sten Ivarsson Annelie Carlsson Jan Neiderud Karin Larsson Björn Jönsson Elisabeth Cedervall Barbro Gustavsson 43 Fariba Vaziri Sani Carina Törn Ahmed Delli Anita Nilsson Anastasia Katsarou Daria La Torre Kristian Lynch Lina Åkesson Peter Ericsson Malin Fex Sabina Lindehammer Barbro Lernmark 5 milj SEK